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PubMed1993

Urinary collagen crosslink excretion: a better index of bone resorption than hydroxyproline in Paget's disease of bone?

The 24 h urinary excretion of the collagen degradation products pyridinoline (Pyr) and deoxypyridinoline (Dpyr) have been proposed as specific and quantitative indices of bone resorption. We compared the value of the urinary excretion of Pyr and Dpyr to that of hydroxyproline (OHP) in 11 patients with Paget's disease of bone before and during treatment with inhibitors of bone resorption, during admission to a metabolic ward and maintenance on a gelatin-free diet. Pyr and Dpyr excretion rates were significantly correlated with those of OHP (r = 0.81 and 0.77, respectively, P < 0.001; n = 106). The rate and degree of suppression of bone resorption were monitored in 6 of the patients similarly treated with intravenous dimethyl-APD at a dose of 4 mg/day for 10 days, by daily measurements of the 24 h urinary excretion of Pyr, Dpyr and OHP. Treatment with dimethyl-APD resulted in a decrease in the three indices of bone resorption. The percentage change from baseline values was similar for the three indices, although changes in Dpyr appeared to follow more closely those of OHP. Our findings suggest that Pyr and Dpyr are useful and specific indices of bone resorption in Paget's disease of bone. They appear to confer no advantage, however, over the traditional determination of the urinary excretion of OHP, in the monitoring of response to treatment of such patients with inhibitors of bone resorption. Further studies are required to establish the value of these new biochemical indices of bone resorption, possibly in more subtle disorders of bone metabolism such as osteoporosis.

Amino Acids↗
PubMed1985

A study of collagen metabolism in cell cultures by fluorometric determination of proline and hydroxyproline.

A technique of derivatization of proline (Pro) and 4-hydroxyproline (Hyp) by 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole permitted the measurement of Pro and Hyp radioactivities, concentrations, and specific activities in the main fractions separated from cultures of fibroblast cells (extracellular collagen and non-collagen proteins, intracellular free Pro and Hyp, Pro- and Hyp-containing peptides, procollagen, and non-collagen proteins). The evaluation of collagen in the medium was obtained from as few as 10(4) cells. The method might advantageously replace [14C] Pro or [3H] Pro incorporation studies. It permits measurement of the size of the Pro pool and the amount of peptides formed by intracellular catabolism of collagen. It demonstrates that the time necessary for a full equilibration of intracellular Pro and intracellular collagen is longer than is generally believed. It avoids the uncertainties of protein labelling, which may vary with uncontrolled variations of the intracellular Pro specific activity.

4-Chloro-7-nitrobenzofurazan↗
PubMed1982

Nitrosation of sarcosine, proline and 4-hydroxyproline by exposure to nitrogen oxides.

The nitrosation of amino acids (sarcosine, proline and 4-hydroxyproline) was investigated in model experiments. The compounds were exposed in crystalline form and as aqueous solutions to defined concentrations of nitrogen oxides (in the range of 1-100 ppm) in the atmosphere of a reaction chamber. Nitrosated amino acids were analysed by GC/TEA after silylation. Generally the extent of nitrosation increased with NOx concentration, reaction time and air humidity. Nitrosation of aqueous amino acid solutions decreased markedly with increasing pH.

Amino Acids↗
PubMed2002

Urinary hydroxyproline as a biomarker of effect after exposure to nitrogen dioxide.

A cross-sectional study was carried out on two groups of subjects differently exposed to nitrogen dioxide in order to test the urinary hydroxyproline ratio (UHP/mg/24 h/m(2)) as a biomarker of effect after exposure to this pollutant. UHP was determined in samples of 58 subjects divided into two groups comparable to as lifestyle and training. The first group was composed of 29 subjects who used to do jogging in urban areas polluted by nitrogen dioxide. The second group was made up of 29 subjects who used to do jogging in non-polluted countryside areas. The mean concentration of UHP of urban joggers was 25.02+/-9.21 mg/24 h/m(2), whereas in those training in the countryside it was 13.78+/-6.68 mg/24 h/m(2). Thus, UHP was higher in subjects training in areas polluted by nitrogen dioxide than in the subjects training in non-polluted areas.

Adolescent↗
PubMed1997

Quantitative separation of 4-hydroxyproline from skeletal muscle collagen by micellar electrokinetic capillary electrophoresis.

The phenylthiohydantoin (PTH) derivatives of 3- and 4-hydroxyproline (Hyp) were separated using micellar electrokinetic capillary electrophoresis (MEKC). The separation protocol was also used to determine Hyp content of bovine skeletal perimysial collagen preparations and whole muscle samples. Amino acids from hydrolyzed tissues were labeled using a two step procedure that involved initial reaction with o-phthalaldehyde (OPA) to modify primary amines followed by their precipitation under acidic conditions. In the second step, imino acids were reacted with phenyl isothiocyanate (PITC). This labeling method was rapid and the Hyp values determined in these biological samples were found to be in close agreement with conventional methods and other published reports.

Animals↗
PubMed1999

Synthesis and evaluation of hydroxyproline-derived isoprenyltransferase inhibitors.

A series of peptidomimetics based on a hydroxyproline scaffold was prepared and evaluated for inhibition of farnesyltransferase and geranylgeranyltransferase I in both enzymatic and cell-based assays. A number of analogs were potent and selective inhibitors of FTase, while one compound (22) was nonselective in the enzymatic assays but eight-fold selective for inhibition of GGTase in the cellular assay (IC50 = 0.39 microM).

3T3 Cells↗
PubMed2001

Glycosylated polyproline II rods with kinks as a structural motif in plant hydroxyproline-rich glycoproteins.

Hydroxyproline-rich glycoproteins (HRGPs) are the major proteinaceous components of higher plant walls and the predominant components of the cell wall of the green alga Chlamydomonas reinhardtii. The GP1 protein, an HRGP of the C. reinhardtii wall, is shown to adopt a polyproline II helical configuration and to carry a complex array of arabinogalactoside residues, many branched, which are necessary to stabilize the helical conformation. The deduced GP1 amino acid sequence displays two Ser-Pro-rich domains, one with a repeating (SP)(x)() motif and the other with a repeating (PPSPX)(x)() motif. A second cloned gene a2 also carries the PPSPX repeat, defining a novel gene family in this lineage. The SP-repeat domains of GP1 form a 100-nm shaft with a flexible kink 28 nm from the head. The gp1 gene encodes a PPPPPRPPFPANTPM sequence at the calculated kink position, generating the proposal that this insert interrupts the PPII helix, with the resultant kink exposing amino acids necessary for GP1 to bind to partner molecules. It is proposed that similar kinks in the higher plant HRGPs called extensins may play a comparable role in wall assembly.

Amino Acid Motifs↗
PubMed1986

Stabilization of collagen fibrils by hydroxyproline.

The substitution of hydroxyproline for proline in position Y of the repeating Gly-X-Y tripeptide sequence of collagen-like poly(tripeptide)s (i.e., in the position in which Hyp occurs naturally) is predicted to enhance the stability of aggregates of triple helices, while the substitution of Hyp in position X (where no Hyp occurs naturally) is predicted to decrease the stability of aggregates. Earlier conformational energy computations have indicated that two triple helices composed of poly(Gly-Pro-Pro) polypeptide chains pack preferentially with a nearly parallel orientation of the helix axes [Nemethy, G., & Scheraga, H.A. (1984) Biopolymers 23, 2781-2799]. Conformational energy computations reported here indicate that the same packing arrangement is preferred for the packing of two poly(Gly-Pro-Hyp) triple helices. The OH groups of the Hyp residues can be accommodated in the space between the two packed triple helices without any steric hindrance. They actually contribute about 1.9 kcal/mol per Gly-Pro-Hyp tripeptide to the packing energy, as a result of the formation of weak hydrogen bonds and other favorable noncovalent interatomic interactions. On the other hand, the substitution of Hyp in position X weakens the packing by about 1.7 kcal/mol per Gly-Hyp-Pro tripeptide. Numerous published experimental studies have established that Hyp in position Y stabilizes an isolated triple helix relative to dissociated random coils, while Hyp in position X has the opposite effect. We propose that Hyp in position Y also enhances the stability of the assembly of collagen into microfibrils while, in position X, it decreases this stability.

Amino Acid Sequence↗
PubMed2005

Different effects of 4-hydroxyproline and 4-fluoroproline on the stability of collagen triple helix.

Differential scanning calorimetry (DSC) analyses of a series of collagen model peptides suggest that 4-hydroxyproline (Hyp) and 4-fluoroproline (fPro) have different effects on the stability of the collagen triple helices according to the sequence of amino acids and stereochemistry at the 4 positions of these imino acids. The thermodynamic parameters indicate that the enhanced stabilities are classified into two different types: the enthalpy term is primarily responsible for the enhanced stability of the triple helix of (Pro-Hyp(R)-Gly)(10), whereas the entropy term dominates the enhanced stability of (Pro-fPro(R)-Gly)(10). The difference between the molecular volumes observed in solution and intrinsic molecular volumes calculated from the crystal structure indicates the different hydration states of these peptides. (Pro-Hyp(R)-Gly)(10) is highly hydrated compared to (Pro-Pro-Gly)(10), which contributes to the larger enthalpy. In contrast, the volume of (Pro-fPro(R)-Gly)(10) shows a smaller degree of hydration than that of (Pro-Pro-Gly)(10). The entropic cost of forming the triple helix of the fPro-containing peptides is compensated by a decrease in an ordered structure of water molecules surrounding the peptide molecule, although the contribution of enthalpy originating from the hydration is reduced. These arguments about the different contribution of entropic and enthalpic terms were successfully applied to interpret the stability of the triple helix of (fPro(S)-Pro-Gly)(10) as well.

Amino Acid Sequence↗
PubMed2001

Understanding the role of stereoelectronic effects in determining collagen stability. 1. A quantum mechanical study of proline, hydroxyproline, and fluoroproline dipeptide analogues in aqueous solution.

The importance of local (intraresidue) effects in determining the stability of the collagen triple helix has been investigated with special reference to the role played by hydroxyproline. To this end the dipeptide analogues of L-proline (ProDA), 4(R)-hydroxy-L-proline (HypDA), and 4(R)-fluoro-L-proline (FlpDA) have been studied by means of quantum mechanical ab initio calculations, taking into account solvent effects by the polarizable continuum model (PCM). Our results confirm that the relative stability of up puckerings of the pyrrolidine ring increases with the electronegativity of the 4(R) substituent (X), whereas down puckerings are favored by 4(S) electronegative substituents. Calculations on model compounds show that this effect is due to the interaction between vicinal C-H bonding and C-X antibonding orbitals. Electronegative substituents on the pyrrolidine ring affect cis-trans isomerism around the peptidic bond, with trans isomers stabilized by 4(R) substituents and cis isomers by 4(S) substituents. Also the hydrogen bonding power of the carbonyl moiety following the pyrrolidine ring is affected by 4(R) substituents, but this effect is tuned by the polarity of the embedding medium. Finally, up puckering favors smaller values of the backbone dihedrals phi and psi. All these results strongly support the proposal that the stability of triple helices containing fluorinated or hydroxylated prolines in Y positions is related to the necessity of having up puckerings in those positions.

Collagen↗
PubMed2003

Triple-helix propensity of hydroxyproline and fluoroproline: comparison of host-guest and repeating tripeptide collagen models.

Peptide models have proved important in defining the structural features of the collagen triple-helix. Some models are based on multiple repeats of a given tripeptide unit, while a host-guest design includes an individual tripeptide unit substituted within a constant repeating Pro-Hyp-Gly framework. In the present study, proline, hydroxyproline, and fluoroproline residues are incorporated in X- or Y-positions of a guest triplet in the host-guest peptide design. All host-guest peptides, including Hyp-Pro-Gly, formed stable triple-helices, even though a triple-helix cannot be formed by (Hyp-Pro-Gly)10. The order of stability Pro-Hyp-Gly > Pro-Pro-Gly > Hyp-Pro-Gly remains the same in all models, while the Pro-Flp-Gly is very stabilizing in a repeating context but destabilizing in a host-guest context. The range of thermal stabilities and calorimetric enthalpies is very small among the five host-guest peptides, consistent with the concept that the effect of one Xaa-Yaa-Gly tripeptide unit in the host-guest system would be less than the much larger variations when there are 10 repeating units. However, a simple additive model based on host-guest peptides predicts a greater stability than experimentally observed. The difference in stability contributions of the same tripeptide unit in host-guest versus repeating tripeptide systems illustrates the impact of sequence environment on stability, and factors that play a role include ring puckering as a consequence of electron inductive effects, residual monomer structure, and native state hydration networks.

Amino Acid Sequence↗
PubMed1987

Synthesis and biological activities of arginine-vasopressin analogues with 4-hydroxyproline in position 7.

Three arginine-vasopressin (AVP) analogues in which the proline residue in position 7 was substituted with 4-hydroxyproline were synthesized by solid-phase techniques, and their biological activities were evaluated by antidiuretic, pressor, and uterotonic bioassays. The [7-trans-4-hydroxy-L-proline]AVP, the 1-desamino[7-trans-4-hydroxy-L-proline]AVP, and the 1-desamino[7-cis-4-hydroxy-L-proline]AVP analogues showed a high antidiuretic and strikingly high uterine activity, a sharp decrease in pressor activity, and a better antidiuretic and uterine to pressor selectivity than the parent compound, arginine-vasopressin. The uterine activities are the highest so far assayed in AVP analogues with replacements in position 7.

Animals↗
PubMed2001

A study on distribution of different hydroxyproline fractions in the bovine ocular tissues.

The purpose of this study was to determine the content of total, free, peptide-bound, protein-bound, soluble- and insoluble collagen hydroxyproline (Hyp) in tissues of bovine eye. The results show that lens had the highest content of free Hyp. This was followed by cornea, retina, iris and aqueous humor. The difference between the Hyp content of lens and iris (p < 0.01) and aqueous humor (p < 0.001) was significant. The peptide-bound Hyp was highest in iris followed by cornea, ciliary body, sclera, lens, aqueous humor and retina. Significant differences (p < 0.001) was observed between the concentration of peptide-bound Hyp of iris and ciliary body, sclera, lens, aqueous humor and retina. Protein-bound Hyp was highest in iris, followed by ciliary body, sclera, cornea, lens, retina and aqueous humor. The difference between the protein-bound Hyp levels of iris and sclera, cornea, lens, retina and aqueous humor was significant (p < 0.001). No peptide-bound and protein-bound Hyp was detected in vitreous humor. Iris had the highest content of total Hyp. This was followed by cornea, ciliary body, sclera, lens, retina, vitreous humor and aqueous humor. The difference in the Hyp content of iris with ciliary body, sclera, lens, retina, vitreous humor and aqueous humor was significant (p < 0.001). Cornea had significantly (p < 0.001) higher content of soluble- and insoluble-collagen Hyp as compared to other tissues. This was followed by ciliary body, sclera, lens, iris and retina. Iris had the highest content of collagen. This was followed by cornea, ciliary body, sclera, lens, retina, vitreous humor and aqueous humor. The difference in the collagen content of iris with ciliary body, sclera, lens, retina, vitreous humor and aqueous humor was significant (p < 0.001).

Animals↗
PubMed2002

Structural basis for the recognition of hydroxyproline in HIF-1 alpha by pVHL.

Hypoxia-inducible factor-1 (HIF-1) is a transcriptional complex that controls cellular and systemic homeostatic responses to oxygen availability. HIF-1 alpha is the oxygen-regulated subunit of HIF-1, an alpha beta heterodimeric complex. HIF-1 alpha is stable in hypoxia, but in the presence of oxygen it is targeted for proteasomal degradation by the ubiquitination complex pVHL, the protein of the von Hippel Lindau (VHL) tumour suppressor gene and a component of an E3 ubiquitin ligase complex. Capture of HIF-1 alpha by pVHL is regulated by hydroxylation of specific prolyl residues in two functionally independent regions of HIF-1 alpha. The crystal structure of a hydroxylated HIF-1 alpha peptide bound to VCB (pVHL, elongins C and B) and solution binding assays reveal a single, conserved hydroxyproline-binding pocket in pVHL. Optimized hydrogen bonding to the buried hydroxyprolyl group confers precise discrimination between hydroxylated and unmodified prolyl residues. This mechanism provides a new focus for development of therapeutic agents to modulate cellular responses to hypoxia.

Amino Acid Motifs↗
PubMed1971

Synthesis and enzymic hydroxylation of protocollagen model peptide containing a hydroxyproline residue.

1. Two protocollagen model peptides, Z-Gly-Pro-Hyp-Gly-(Pro-Pro-Gly)(5) (Z, benzyloxycarbonyl) and AOC-(Pro-Pro-Gly)(6) (AOC, tert.-pentyloxycarbonyl), were synthesized and hydroxylated with protocollagen proline hydroxylase. 2. The two model peptides were hydroxylated equally. The results suggest that the hydroxyl group of hydroxyproline contained in the N-terminal region of the peptide has no effect on the enzymic hydroxylation of the model peptide.

Amino Acid Sequence↗
PubMed1994

The secreted cathepsin L-like proteinases of the trematode, Fasciola hepatica, contain 3-hydroxyproline residues.

The cysteine proteinases synthesized by the adult stage of the trematode Fasciola hepatica were found to be a very heterogeneous group of proteins as demonstrated by one- and two-dimensional gel analyses. N-terminal amino acid sequencing indicated the presence of at least two distinct gene products among the secreted cysteine proteinases. Enzymic studies and peptide sequence analysis of the excreted/secreted cysteine proteinases suggested a close relationship to the plant thiol cathepsins and the mammalian cathepsin L subfamily. The cloning of a representative cDNA for a putative Fasciola cathepsin confirmed similarities to the cathepsin L subfamily but revealed low identity with the cathepsin-like proteinases of the related trematode, Schistosoma, nematode cathepsins and the mammalian cathepsin B subfamily. Furthermore, peptide and protein sequencing revealed the modification of certain highly conserved prolines to unusual 3-hydroxyproline derivatives. This is the first report of modified prolines in any proteinase. This finding, as well as the high activities of these cathepsins at neutral to alkaline pH values, raises a number of questions as to the physiological function of these thiol cathepsins and their interaction with host tissues.

Amino Acid Sequence↗
PubMed1976

Urinary excretion of peptides and of hydroxyproline in Wilson's disease.

1. A study has been made of peptide excretion in twenty cases of Wilson's disease, ligand-exchange column chromatography being used to separate peptides from free amino acids. Previous reports of excess of peptide output in the disease were confirmed and the excess was shown to be highly significant statistically. 2. A considerable fraction of the excess of peptide output was shown to consist of hydroxyproline-containing peptides derived from collagen degradation. 3. The method of rank correlation showed that the difference both in free amino acid and peptide-bound amino acid output in cases of Wilson's disease and in control subjects was mainly quantitative; the pattern of amino acid excretion was qualitatively similar in both groups. 4. Evidence is presented that the increase copper output in the urine in the disease is not secondary to peptiduria.

Adolescent↗